Genetic Analysis of the Induction and Morphogenesis of the Inner Ear

描述（由申请人提供）：当胚胎后脑两侧的外胚层的两个区域形成称为耳基板的增厚的上皮时，内耳开始发育。组成膜状内耳的所有细胞类型，包括机械感觉毛细胞和支配它们的神经元，都是耳基板细胞的后代。因此，耳基板形成中的任何扰动都可能对内耳的形成和功能产生严重后果。此外，据估计，高达39%的先天性听力和平衡障碍病例与内耳畸形有关。本项目的长期目标是了解诱导耳基板所需的分子途径，这将增强我们对与内耳畸形相关的先天性听力和平衡障碍的理解。在这里，我们提出了一种遗传学的方法来阐明受体酪氨酸激酶信号传导，包括成纤维细胞生长因子（FGF）信号传导，在耳基板诱导的拮抗剂Sprouty家族的作用。目的1）分析Spry1和Spry2基因在耳基板诱导过程中的冗余功能，并检验Spry1和Spry2在耳基板诱导过程中冗余功能限制FGF信号传导范围的假设。目的2）验证Spry1和Spry2在耳基板诱导的早期阶段功能冗余的假设，以及在Spry1和Spry2基因功能缺失的情况下，有助于耳基板诱导的其他信号通路将被错误调节的假设。目的3）确定Spry1和Spry2基因在耳基板诱导过程中的基因充足性，并验证Spry1和Spry2的组织特异性表达对于耳基板的正确诱导是关键的假设。 公共卫生相关性：我们提出了一种遗传学方法来探索诱导胚胎祖细胞产生内耳所需的信号。这项研究应该加强我们对内耳畸形导致的先天性听力和平衡障碍的理解，例如Michel和Mondini型发育不全，并应该为再生医学提供内耳祖细胞的尝试。

DESCRIPTION (provided by applicant): Development of the inner ear begins when two regions of ectoderm on either side of the embryonic hindbrain form thickened patches of epithelium called the otic placodes. All of the cell types that compose the membranous inner ear, including the mechanosensory hair cells and the neurons that innervate them, are descendents of cells in the otic placode. Consequently, any perturbations in formation of the otic placode can have severe consequences on the formation and function of the inner ear. Furthermore, it is estimated that up to 39% of cases of congenital hearing and balance disorders are associated with malformation of the inner ear. The long-term goal of this project is to understand the molecular pathways required for induction of the otic placode, which should enhance our understanding of those congenital hearing and balance disorders associated with inner ear malformation. Here we propose a genetic approach to elucidate the role of the Sprouty family of antagonists of receptor tyrosine kinase signaling, including Fibroblast Growth Factor (FGF) signaling, in otic placode induction. The specific aims of this proposal are: Aim 1) To analyze the redundant functions of the Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that Spry1 and Spry2 function redundantly to limit the range of FGF signaling during induction of the otic placode. Aim 2) To test the hypothesis that Spry1 and Spry2 function redundantly at an early step in otic placode induction, and that other signaling pathways that contribute to otic placode induction will be misregulated in the absence of both Spry1 and Spry2 gene function. Aim 3) To determine the gene-sufficiency of the individual Spry1 and Spry2 genes during otic placode induction and to test the hypothesis that the tissue-specific expression of Spry1 and Spry2 is critical for proper induction of the otic placode. PUBLIC HEALTH RELEVANCE: We propose a genetic approach to explore the signals required for induction of the embryonic progenitor cells that give rise to the inner ear. This study should enhance our understanding of congenital hearing and balance disorders resulting from malformation of the inner ear, such as Michel- and Mondini-type aplasia, and should inform attempts to generate progenitor cells of the inner ear for regenerative medicine.